The present invention relates to a retinoid-related receptor function regulating agent comprising a 1,3-azole derivative or its salt, which is useful for treating or preventing diabetes, hyperlipidemia, impaired glucose tolerance, etc.
So far, 1,3-azole derivatives have been report in various references. For example, a compound having an anti-inflammatory effect (e.g., JP-A-4-154773, U.S. Pat. No. 5,342,851), a compound having a platelet aggregation-inhibiting effect (e.g., U.S. Pat. No. 5,342,851), a compound having an active oxygen-inhibiting effect (e.g., WO 9209586, Journal of Medicinal Chemistry, Vol.38, p. 353 1(1995), a compound having a thrombolytic effect (e.g., JP-B-49-32853) and a compound having a phospholipase IV-inhibiting effect (e.g., WO9808830) have been reported. Also, they have been reported as a liquid crystal composition (EP-A 439170) and a raw material compound for producing a vasopressin receptor ligand (WO9534540). Further, 1,3-azole carboxylic acid derivatives are described in Chemical Abstracts, vol.107, 23273h (1987), Chemical Abstracts, vol.113, 6239h (1990) and Chemical Abstracts, vol.120, 190974n (1994).
Some 1,3-azole derivatives are marketed as reagents by BIONET (Cornwall, England).
However, there has been no report that these compounds have a retinoid-related receptor function regulating effect, and exhibit excellent effects in treating or preventing diabetes, hyperlipidemia, impaired glucose tolerance, etc.
On the other hand, retinoid-related receptor function regulating agents are reported in JP-A-9-71566 (WO 9702244, EP838453), etc. However, there has been no report that these compounds exhibit excellent effects in treating or preventing hyperlipidemia, impaired glucose tolerance, etc.
Peroxisome proliferator-activated receptor gamma (PPARxcex3), a member of the intranuclear hormone receptor superfamily, which is typically exemplified by steroid hormone receptors and thyroid hormone receptors, plays an important role as a master regulator in the differentiation of adipose cells with its expression induced in the very early stage of adipose cell differentiation. PPARxcex3 forms a dimer with the retinoid X receptor (RXR) by binding to a ligand, and binds to a responsive site of the target gene in the nucleus to directly control (activate) transcription efficiency. In recent years, it has been revealed that 15-deoxy-xcex9412.14 prostaglandin J2, a metabolite of prostaglandin D2, serves as an endogenous ligand for PPARxcex3. Further it has been revealed that a class of insulin sensitivity enhancers, typically exemplified by thiazolidinedione derivatives, possess ligand activity for PPARxcex3, and that its potency is proportional to its hypoglycemic action or adipose cell differentiation-promoting action [Cell, vol. 83, p. 803 (1995): the Journal of Biological Chemistry, vol. 270, p. 12953 (1995); Journal of Medicinal Chemistry, vol. 39, p. 655 (1996)].
Many agents have been employed as agents for treating diabetes, hyperlipidemia, arteriosclerosis, etc. However, they are not satisfactory in terms of their therapeutic effects or reduced side effects, and the development of agents improved in these terms is strongly desired.
The inventors have discovered that a certain 1,3-azole derivative or its salt has an unexpectedly excellent PPAR ligand activity, and that it is useful as an agent for preventing or treating diabetes, hyperlipidemia, arteriosclerosis, etc. Based on these findings, the inventors made further investigations to complete the present invention.
Thus, the present invention relates to:
(1) a retinoid-related receptor function regulating agent comprising a 1,3-azole derivative represented by formula (I): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; X is O, S or a group represented by the formula: xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen or an optionally substituted alkyl group; A is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
are excluded, or its salt.
(2) a function regulating agent according to the above (1) wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group which does not contain a nitrogen atom, each of which may be substituted.
(3) a function regulating agent according to the above (1) which is an agent for preventing or treating diabetes.
(4) a function regulating agent according to the above (1) which is a lipid metabolism-improving agent.
(5) a function regulating agent according to the above (1) which is an agent for preventing or treating hyperlipidemia.
(6) a function regulating agent according to the above (1) which is an agent for preventing or treating obesity.
(7) a function regulating agent according to the above. (1) which is an anti-obesity agent.
(8) a function regulating agent according to the above (1) which is an insulin sensitivity enhancer.
(9) a function regulating agent according to the above (1) which is an insulin resistance improving agent.
(10) a function regulating agent according to the above (1) which is an agent for preventing or treating impaired glucose tolerance.
(11) an oxazole derivative represented by formula (I-1): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formula: 
wherein both R8s are NH2, OH, phenoxy, OCH3, 
are excluded, or its salt.
(12) an oxazole derivative or its salt according to the above (11) wherein the formula is 
(13) an oxazole derivative represented by formula (I-2): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
are excluded, or its salt.
(14) an oxazole derivative or its salt according to the above (13) wherein R2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group except for a non-aromatic hydrocarbon group which is substituted by an optionally esterified carboxyl group, and R3 is a group represented by the formula: xe2x80x94OR5.
(15) an oxazole derivative represented by formula (I-3): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
are excluded, or its salt.
(16) an oxazole derivative according to the above (15) wherein A1 is a phenyl group having a xe2x80x94COR3 group in a meta- or para-position, provided that compounds represented by the formulae: 
are excluded, or its salt.
(17) an oxazole derivative or its salt according to the above (16) wherein R3 is OH.
(18) an imidazole derivative represented by formula (I-4): 
wherein R1 is an aromatic hydrocarbon group or aromatic heterocyclic group, each of which may be substituted; R2xe2x80x2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that a compound represented by the formula: 
is excluded, or its salt.
(19) an imidazole derivative or its salt according to the above (18) wherein R1 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by sulfo group.
(20) an imidazole derivative represented by formula (I-5): 
wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2xe2x80x2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
are excluded, or it is salt.
(21) an imidazole derivative according to the above (20) wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon, and said aromatic hydrocarbon group does not form a condensed ring, provided that a compound represented by the formula: 
is excluded, or its salt.
(22) an imidazole derivative or its salt according to the above (21) wherein R3 is a group represented by the formula xe2x80x94OR5.
(23) a thiazole derivative represented by formula (I-6): 
wherein R1xe2x80x2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a group having an intervening hetero atom; R2xe2x80x3 is hydrogen or an alkyl group; A2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon substituted by a group having an intervening hetero atom; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6. and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
wherein R9 is methoxy group, methyl group, chlorine, t-butyl group or trifluoromethyl group and, 
and its HBr salt are excluded, or its salt.
(24) a thiazole derivative or its salt according to the above (23) wherein R1xe2x80x2 is an aromatic hydrocarbon group having at least two substituents.
(25) a thiazole derivative or its salt according to the above (23) wherein R1xe2x80x2 is phenyl group having a substituent in an ortho- or meta-position.
(26) a thiazole derivative represented by formula (I-7): 
wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2 is hydrogen or an optionally substituted hydrocarbon group; A2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a group having an intervening hetero atom; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
wherein the combination of the definitions is any of the following: both of R10 and R11 are hydrogen and R3 is hydroxyl group or methoxy group; R10 is chlorine substituting at 2- or 4-position, R11 is hydrogen or R3 is hydroxyl group or methoxy group; R10 is chlorine substituting at 2- or 3-position, R11 is chlorine substituting at 4-position, and R3 is hydroxyl group or methoxy group; R10 is fluorine substituting at 4-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group; R10 is methoxy group substituting at 4-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group; R10 is CF3 group substituting at 3-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group, 
are excluded, or its salt.
(27) a thiazole derivative or its salt according to the above (26) wherein R1xe2x80x3 is an aromatic hydrocarbon group having at least two substituents.
(28) a thiazole derivative or its salt according to the above (27) wherein A2 is phenyl group having a substituent xe2x80x94COR3 in an ortho-position.
(29) a thiazole derivative or its salt according to the above (26) wherein R2 is an optionally substituted hydrocarbon group.
(30) a thiazole derivative represented by formula (I-8): 
wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2 is hydrogen or an optionally substituted hydrocarbon group; A3 is an optionally substituted aromatic hydrocarbon group; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that a compound represented by the formula: 
is excluded, or its salt.
(31) a thiazole derivative or its salt according to the above (30) wherein R1xe2x80x3 is a substituted aromatic hydrocarbon group.
(32) at least one compound selected from the group consisting of:
i) 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoic acid,
ii) 4-[4-4-trifuoromethylphenyl)-2-oxazolyl]benzoic acid,
iii) 4-[4-(4-trifuoromethylphenyl)-2-thiazolyl]benzoic acid,
iv) 4-[4-(4-trifuoromethoxyphenyl)-2-thiazolyl]benzoic acid,
v) 3-[4-(4-isopropylphenyl)-2-thiazolyl]benzoic acid,
vi) 3-[4-(4-ethoxyphenyl)-2-thiazolyl]benzoic acid,
vii) 4-[2-(4-trifuoromethylphenyl)-5-oxazolyl]benzoic acid,
viii) 4-[2-(4-trifuoromethylphenyl)-5-thiazolyl]benzoic acid,
ix) 3-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoic acid and,
x) 3-[4-(2,5-dimethyl-3-thienyl)-2-thiazolyl]benzoic acid, or its salt.
(33) a method for regulating a retinoid-related receptor function comprising administering a 1,3-azole derivative represented by formula (I): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; X is O, S or a group represented by the formula: xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen or an optionally substituted alkyl group; A is an optionally substituted aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5xe2x80x94 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form, a ring, provided that compounds represented by the formulae: 
are excluded, or its salt.
(34) use of a 1,3-azole derivative represented by formula (I): 
wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; X is O, S or a group represented by the formula: xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen or an optionally substituted alkyl group; A is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
are excluded, or its salt for producing a pharmaceutical for regulating a retinoid-related receptor function.
In the formula (I), R1 and A are an optionally substituted aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted.
Examples of the aromatic hydrocarbon group in the optionally substituted aromatic hydrocarbon group for R1 and A include an aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, azulenyl, biphenylyl and the like, with phenyl, 1-naphthyl and 2-naphthyl being preferred.
Examples of the aromatic heterocyclic group in the optionally substituted aromatic heterocyclic group for R1 and A include a 5 to 7-membered aromatic monocyclic heterocyclic group having as a ring constituting atoms, in addition to carbon atoms, 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms or an aromatic condensed heterocyclic group.
Concrete examples of the aromatic heterocyclic group include an aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl; a bicyclic or tricyclic aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbonylyl, xcex2-carbonylyl, xcex3-carbonylyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl, indolydinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo]4,3-a]pyridyl and 1,2,4,-triazolo]4,3-b]pyridazinyl. Among these, regarding R1, an aromatice heterocyclic group which does not contain a nitrogen atome is preferable, and a thienyl group and a furyl group are more preferable. Regarding A, an aromatic monocyclic heterocyclic group is preferable, and a pyridyl group and a thienyl group are more perferable.
Examples of the substituent in the above aromatic hydrocarbon group and aromatic heterocyclic group include optionally halogenated alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkynyl g up having 2 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, cycloalkenyl group having 3 to 7 carbon atoms, cycloalkynyl group having 3 to 7 carbon atoms, aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.), 5- to 6-membered heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), 5- to 6-membered non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, etc.), aralkyl group having 7 to 19 carbon atoms (benzyl, benrzhydryl, trityl, etc.), amino group optionally mono- or di-substituted by an alkyl having 1 to 4 carbon atoms or an acyl having 2 to 8 carbon atoms (e.g., alkanoyl having 2 to 8 carbon atoms), amidino group, an acyl group having 2 to 8 carbon atoms (e.g., alkanoyl having 2 to 8 carbon atoms), carbamoyl group optionally mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, sulfamoyl group optionally mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, an optionally esterified carboxyl group (e.g., alkoxycarbonyl group having 2 to 8 carbon atoms), hydroxyl group, optionally halogenated alkoxy group having 1 to 6 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, cycloalkyloxy group having 3 to 7 carbon atoms, aralkyloxy group having 7 to 9 carbon atoms, aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy, naphthyloxy, etc.), thiol group, alkylthio group having 1 to 6 carbon atoms, aralkylthio group having 7 to 19 carbon atoms (e.g., benzylthio, etc.), arylthio group having 6 to 14 carbon atoms (e.g., phenylthio, naphthylthio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.) and the like. Among these, regarding the substituent on R1, a substituent which does not form a condensed ring is preferable, and an alkyl group having 1 to 6 carbon atoms, a halogen atom or a halogen atom-containing substituent is more preferable. Regarding t substituent on A, a substituent which does not bind via a hetero atom is preferable.
R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring.
R2 is hydrogen or an optionally substituted hydrocarbon group in the same manner as R5. Examples of the optionally substituted hydrocarbon group in R2 and R5 include a hydrocarbon group having 1 to 24 carbon atoms, such as an aliphatic hydrocarbon group having 1 to 14 carbon atoms, an alicyclic hydrocarbon group having 3 to 10 carbon atoms, an alicyclic hydrocarbon group having 3 to 10 carbon atomsxe2x80x94an aliphatic hydrocarbon having 1 to 14 carbon atoms, an aromatic aliphatic hydrocarbon group having 7 to 19 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms. Among these, regarding R2, an aliphatic hydrocarbon group having 1 to 14 carbon atoms, an alicyclic hydrocarbon group having 3 to 10 carbon atoms and an aromatic hydrocarbon group having 6 to 14 carbon atoms are preferably used, especially an alkyl group having 1 to 8 carbon atoms is preferably used. Regarding R5, an aliphatic hydrocarbon having 1 to 14 carbon atoms an dan aromatic aliphatic hydrocarbon group having 7 to 19 carbon atoms are preferably used, especially an alkyl group having 1 to 8 carbon atoms and an aralkyl-group having 7 to 19 carbon atoms are preferably used.
Examples of an aliphatic hydrocarbon group having 1 to 14 carbon atoms include an alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl and octyl, an alkenyl group having 2 to 8 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl; an alkynyl group having 2 to 8 carbon atoms such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl and 1-octynyl.
Examples of an alicyclic hydrocarbon having 3 to 10 carbon atoms include a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a cycloalkenyl group having 5 to 7 carbon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadienyl.
Examples of an alicyclic hydrocarbon group having 3 to 10 carbon atomsxe2x80x94aliphatic hydrocarbon having 1 to 14 carbon atoms include a cycloalkyl having 3 to 7 carbon atomsxe2x80x94alkyl group having 1 to 14 carbon atoms, a cycloalkenyl having 5 to 7 carbon atomsxe2x80x94alkyl group having 1 to 14 carbon atoms, etc. Concrete examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylmethyl, cyclohexylpropyl, cycloheptylethyl, cycloheptylethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, etc.
Concrete examples of an aromatic aliphatic hydrocarbon group having 7 to 19 carbon atoms include an aralkyl group having 7 to 19 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, xcex1-naphthylmethyl, xcex1-naphthylethyl, xcex2-naphthylmethyl and xcex2-naphthylethyl; an arylalkenyl group having 8 to 13 carbon atoms such as styryl and 2-(2-naphthylvinyl).
Examples of an aromatic hydrocarbon having 6 to 14 carbon atoms include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, etc.
The substituent in the above hydrocarbon groups is exemplified by that similar to the substituent on the aromatic hydrocarbon and the aromatic heterocyclic groups defined for R1 and A. The substituent in R5 is preferably a halogen atom and an alkoxy group having 1 to 6 carbon atoms.
R4 is hydrogen or an optionally substituted alkyl group, with hydrogen being particularly preferred. Examples of the alkyl group in an optionally substituted alkyl group include a straight-chain or branched alkyl group having, 1 to 16 carbon atoms. Preferred examples include a straight-chain or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
Examples of a substituent on such alkyl group include an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.), a 5- to 6-membered aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), a 5- to 6-membered non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, etc.), an aralkyl group having 7 to 19 carbon atoms (benzyl, benzhydryl, trityl, etc.), amino group optionally mono- or di-substituted by an alkyl having 1 to 4 carbon atoms or an acyl having 2 to 8 carbon atoms (e.g., alkanoyl having 2 to 8 carbon atoms), amidino group, an acyl group having 2 to 8 carbon atoms (e.g., alkanoyl having 2 to 8 carbon atoms), carbamoyl group optionally mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms, sulfamoyl group optionally mono- or di-substituted by an alkyl having 1 to 4 carbon atoms, an optionally esterified carboxyl group (e.g., alkoxycarbonyl group having 2 to 8 carbon atoms), hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms (e.g., phenoxy, naphthyloxy, etc.), thiol group, an alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 19 carbon atoms (e.g., benzylthio, etc.), an arylthio, group having 6 to 14 carbon atoms (e.g., phenylthio, naphthylthio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.).
As described above, R6 and R7 are hydrogen or an optionally substituted hydrocarbon group, respectively. The optionally substituted hydrocarbon group defined for R6 and R7 is exemplified by that similar to the optionally substituted hydrocarbon-group defined for R2 and R5.
Examples of a N-containing heterocyclic group formed by R6 and R7 together with an adjacent nitrogen atom include a 5- to 7-membered ring. Concrete examples include 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl.
A compound represented by formula (I) includes, for instance, compounds represented by the following formulae: 
wherein each, symbol has the same meanings as defined above.
Among the compound represented by formula (I), preferred is a compound wherein R1 is phenyl, thienyl, furyl or pyridyl (preferably phenyl or thienyl, more preferably phenyl), each of which may have 1 to 5 (preferably 1 to 3, more preferably 1 to 2) substituents selected from a halogen atom, an optionally halogenated alkyl group having 1 to 6 carbon atoms and an optionally halogenated alkoxy group having 1 to 6 carbon atoms,
R2 is hydrogen atom,
X is O or S,
A is phenyl or thienyl (preferably phenyl),
R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an alkyl group having 1 to 6 carbon atoms (preferably hydrogen); and especially preferred is at least one compound selected from:
i) 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoic acid,
ii) 4-[4-(4-trifluoromethylphenyl)-2-oxazolyl]benzoic acid,
iii) 4-[4-(4-trifluoromethylphenyl)-2-thiazolyl]benzoic acid,
iv) 4-[4-(4-trifluoromethoxyphenyl)-2-thiazolyl]benzoic acid,
v) 3-[4-(4-isopropylphenyl)-2-thiazolyl]benzoic acid,
vi) 3-[4-(4-ethoxyphenyl)-2-thiazolyl]benzoic acid,
vii) 4-[2-(4-trifluoromethylphenyl)-5-oxazolyl]benzoic acid,
viii) 4-[2-(4-trifluoromethylphenyl)-5-thiazolyl]benzoic acid,
ix) 3-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoic acid, and
x) 3-[4-(2,5-dichloromethyl-3-thienyl)-2-thiazolyl]benzoic acid, or its salt.
Among the compounds represented by formula (I), the followings are novel compounds:
an oxazole derivative represented by formula (I-1): 
xe2x80x83wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formula: 
xe2x80x83wherein both R8s are NH2, OH, phenoxy, OCH3, 
xe2x80x83are excluded, or its salt;
an oxazole derivative represented by formula (I-2): 
xe2x80x83wherein R1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally, substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
xe2x80x83are excluded, or its salt;
an oxazole derivative represented by formula (I-3): 
xe2x80x83wherein R1 is an aromatic hydrocarbon group or aromatic heterocyclic group, each of which may be substituted; R2 is hydrogen or an optionally substituted hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
xe2x80x83are excluded, or its salt;
an imidazole derivative represented by formula (I-4): 
xe2x80x83wherein R1 is an aromatic hydrocarbon group or aromatic heterocyclic group, each of which may be substituted; R2xe2x80x2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that a compound represented by the formula: 
xe2x80x83is excluded, or its salt;
an imidazole derivative represented by formula (I-5): 
xe2x80x83wherein Rxe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2xe2x80x2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group; A1 is an aromatic hydrocarbon group or thienyl group, each of which may be substituted; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
xe2x80x83are excluded, or its salt;
a thiazole derivative represented by formula (I-6): 
xe2x80x83wherein R1xe2x80x2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a group having an intervening hetero atom; R2xe2x80x3 is hydrogen or an alkyl group; A2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a group having an intervening hetero atom; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon, group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
xe2x80x83wherein R9 is methoxy group, methyl group, chlorine, t-butyl group or trifluoromethyl group and, 
xe2x80x83and its HBr salt are excluded, or its salt;
a thiazole derivative represented by formula (I-7): 
xe2x80x83wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2 is hydrogen or an optionally substituted hydrocarbon group; A2 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a group having an intervening hetero atom; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that compounds represented by the formulae: 
xe2x80x83wherein the combination of the definitions is any of the following: both of R10 and R11 are hydrogen atoms and R3 is hydroxyl group or methoxy group; R10 is chlorine substituting at 2- or 4-position, R11 is hydrogen or R3 is hydroxyl group or methoxy group;, R10 is chlorine substituting at 2- or 3-position, R11 is chlorine substituting at 4-position and R3 is hydroxyl group or methoxy group; R10 is fluorine substituting at 4-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group; R10 is a methoxy group substituting at 4-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group; R10 is a CF3 group substituting at 3-position, R11 is hydrogen and R3 is hydroxyl group or methoxy group, 
xe2x80x83are excluded, or its salt; and
a thiazole derivative represented by formula (I-8): 
xe2x80x83wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon group; R2 is hydrogen or an optionally substituted hydrocarbon group; A3 is an optionally substituted aromatic hydrocarbon group; R3 is a group represented by the formula: xe2x80x94OR5 wherein R5 is hydrogen or an optionally substituted hydrocarbon group, or xe2x80x94NR6R7 wherein R6 and R7 are same or different and each is hydrogen or an optionally substituted hydrocarbon group, or R6 and R7 may be taken together with an adjacent nitrogen atom to form a ring, provided that a compound represented by the formula: 
xe2x80x83is excluded, or its salt.
A compound represented by formula (I-1) is preferably an oxazole derivative represented by the formula: 
or its salt.
A compound represented by formula (I-2) is preferably an oxazole derivative wherein R2 is hydrogen or an optionally substituted non-aromatic hydrocarbon group except for a non-aromatic hydrocarbon group which is substituted by an optionally esterified carboxyl group and R3 is a group represented by the formula: xe2x80x94OR5 or its salt
A compound represented by formula (I-3) is preferably an oxazole derivative wherein A1 is a phenyl group having a xe2x80x94COR3 group in a meta- or para-position, provided that compounds represented by the formulae: 
are excluded, or its salt; and more preferably an oxazole derivative wherein R3 is OH, or its salt.
A compound represented by formula (I-4) is preferably an imidazole derivative wherein R1 is an optionally substituted aromatic hydrocarbon group except for an aromatic hydrocarbon group substituted by a sulfo group, or its salt.
A compound represented by formula (I-5) is preferably an imidazole derivative wherein R1xe2x80x3 is an optionally substituted aromatic hydrocarbon, and said aromatic hydrocarbon group does not form a condensed ring, provided that a compound represented by the formula: 
is excluded, or its salt; and more preferably an imidazole derivative wherein R3 is a group represented by the formula: xe2x80x94OR5.
A compound represented by formula (I-6) is preferably a thiazole derivative wherein R1xe2x80x2is an aromatic hydrocarbon group having at least two substituents, or its salt; or a thiazole derivative wherein R1xe2x80x2 is phenyl group having a substituent in an ortho- or meta-position, or its salt.
A compound represented by formula (I-7) is preferably a thiazole derivative wherein R2 is an optionally substituted hydrocarbon group, or its salt; or a thiazole derivative wherein R1xe2x80x3 is an aromatic hydrocarbon group having at least two substituents, or its salt; and more preferably a thiazole derivative wherein A2 is phenyl group having a substituent xe2x80x94COR3 group in an ortho-position, or its salt.
A compound represented by formula (I-8) is preferably a thiazole derivative wherein R1xe2x80x3 is a substituted aromatic hydrocarbon group, or its salt.
A salt of a compound represented by formula (I) is preferably a pharmacologically acceptable salt, and exemplified by a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
Examples of a preferred salt with an inorganic base include an alkaline metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; as well as an aluminum salt and an ammonium salt.
Examples of a preferred salt with an organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.
Examples of a preferred salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and, the like.
Examples of a preferred salt with an organic include a salt, with formic acid, acetic acid, trifluoroaceticd acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
Examples of a preferred salt with a basic amino acid include a salt with arginine, lysine, ornithine and the like, while examples of a preferred salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like.
Among the above salts, preferred are a sodium salt, a potassium salt, a hydrochloride and the like.
A compound represented by formula (I) or its salt (hereinafter simply abbreviated as Compound (I)) can be formulated in accordance with a known method, if necessary by admixing with a pharmacologically acceptable carrier, into a pharmaceutical composition of the invention, which can be safely administered to a mammal (e.g., human, cattle, horse, pig, monkey, dog, rabbit, cat, rat, mouse, etc.).
As the pharmacologically acceptable carrier, various organic and inorganic carriers commonly used as a pharmaceutical material are employed. These are incorporated as an excipient, a lubricant, a binder and a disintegrant for a solid dosage form; and a solvent, a solubilizer, an osmotic agent, a buffering agent and a soothing agent for a liquid dosage form. A pharmaceutical additive such as a preservative, an antioxidant, a colorant and a sweetener, may also be employed if necessary.
Preferred examples of the excipient include lactose, sugar, D-mannitol, D-sorbitol, starch, gelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica.
Preferred examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone.
Preferred examples of the disintegrant include lactose, sugar, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, crosscarmelose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose.
Preferred examples of the solvent include water for injection, physiological saline, Ringer""s solution, an alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium. salicylate, sodium acetate.
Preferred examples of the suspending agent include a surfactant such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopbropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate; a hydrophilic polymer such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose; polysolvate and polyoxyethylene hardened castor oil.
Preferred examples of the osmotic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose.
Preferred examples of the buffering agent include a buffer solution of phosphate, acetate, carbonate, citrate.
Preferred examples of the soothing agent include benzyl alcohol.
Preferred examples of the preservative include p-oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid.
Preferred examples of the antioxidant include sulfite, ascorbate.
Preferred examples of the colorant include a water-soluble edible tar dye (e.g., edible red No.2 and No.3, edible yellow No.4 and No.5, edible blue No.1 and No.2), a water-insoluble lake dye (e.g., an aluminum salt of the above water-soluble edible tar dye), a naturally-occurring dye (e.g., xcex2-carotene, chlorophyll, iron oxide red) and the like.
Preferred examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
A pharmaceutical composition of the invention can be safely administered as an oral preparation such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; and as a parenteral preparation such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip infusions, external application forms (e.g., nasal preparations, percutaneous preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets and drip infusions.
A pharmaceutical composition of the invention can be prepared by a conventional, method in the field of pharmaceutical techniques, for example, by a method described in Japanese Pharmacopoeia. A typical method for preparing a pharmaceutical composition is detailed below.
For example, an oral preparation is prepared by adding to an active ingredient, for example, an excipient, a disintegrant, a binder or a lubricant, and compression molding, if necessary followed by coating using a coating base by a per se known method for the purpose of taste masking, enteric coating or sustained release.
Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained release film coating base.
As the sugar coating base, a sugar is employed. Further, one or at least two species selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba was can be used in combination.
Examples of the water-soluble film coating base include a cellulose polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose and methylhydroxyethyl cellulose; a synthetic polymer such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [EUDRAGIT E (trade name), Rohm Pharma] and polyvinyl pyrrolidone; a polysaccharide such as pullulan.
Examples of the enteric film coating base, include a cellulose polymer such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose and cellulose acetate phthalate; an acrylic acid polymer such as methacrylic acid copolymer L [EUDRAGIT L (trade name), Rohm Pharma], methacrylic acid copolymer LD [EUDRAGIT L-30D55 (trade name), Rohm Pharma], methacrylic acid copolymer S [EUDRAGIT S (trade name), Rohm Pharma]; and a naturally-occurring material such as shellac.
Examples of the sustained release film coating base include a cellulose polymer such as ethyl cellulose; and an acrylic acid polymer such as an aminoalkylmethacrylate copolymer RS [EUDRAGIT RS (trade name), Rohm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [EUDRAGIT NE (trade name), Rohm Pharma].
Two or more of these coating bases described above may be used as being admixed at a suitable ratio. At the time of coating, a shading agent such as titanium oxide and red ferric oxide may be used.
Injections can be prepared by dissolving, suspending or emulsifying an active ingredient in an aqueous solvent (e.g. distilled water, physiological saline, Ringer""s solution) or in an oily solvent (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil and corn oil; propylene glycol) together with a dispersant (e.g. polysorbate 80, polyoxyethylene hardened castor oil 60), polyethylene glycol, carboxymethyl cellulose, sodium alginate), a preservative (e.g., methylparaben, propylparaben, benzylalcohol, chlorobutanol, phenol), an osmotic agent (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose). In this case, additives such as solubilizers (e.g., sodium salicylate, sodium acetate), a stabilizer (e.g., human serum albumin) and a soothing agent (e.g., benzyl alcohol) can be used, if necessary.
Compound (I) has a retinoid-related receptor function regulating effect (e.g., retinoid-related receptor function activating effect, retinoid-related receptor function suppressing effect; preferably retinoid-related receptor function activating effect). A retinoid-related receptor used herein means a DNA-binding transcription factor, included in intranuclear receptors, whose ligand is a signal molecule such as an lipid-soluble vitamin, and may be a monomer receptor, a homodimer receptor or a heterodimer receptor. Examples of the monomer receptor include a retinoid O receptor (hereinafter sometimes abbreviated as ROR) xcex1 (GenBank Accession No.L14611), ROR xcex2 (GenBank Accession No.L14160), ROR xcex3 (GenBank Accession No.U16997); Rev-erb xcex1 (GenBank Accession No.M24898); Rev-erb xcex2 (GenBank Accession No.L31785); ERR xcex1 (Gen Bank Accession No.X51416), ERR xcex2 (GenBank Accession No.X51417); Ftz-FI xcex1 (GenBank Accession No.S65876), Ftz-FI xcex2 (GenBank Accession No.M81385); TIx (GenBank Accession No.S77482);. GCNF (GenBank Accession No.U14666).
Examples of the homodimer receptor include a, homodimer formed from a retinoid X receptor (hereinafter sometimes abbreviated as RXR) xcex1 (GenBank Accession No.X52773), RXR xcex2 (GenBank Accession No.M84820), RXR xcex3 (GenBank Accession No.U38480); COUPxcex1 (GenBank Accession No.X12795), COUPxcex2 (GenBank Accession No.M64497), COUPxcex3 (GenBank Accession No.X12794); TR2xcex1 (GenBank-Accession No.M29960), TR2xcex2 (GenBank Accession No.L27586); or HNF4xcex1 (GenBank Accession No.X76930), HNF4xcex3 (GenBank Accession No.Z49826) and the like.
Examples of the heterodimer receptor include a heterodimer formed from a retinoid X receptor described above (RXRxcex1, RXRxcex2 or RXRxcex3) and one receptor selected from a retinoid A receptor (hereinafter sometimes abbreviated as RAR) xcex1 (GenBank Accession No.X06614), RAR xcex2 (GenBank Accession No.Y00291), RAR xcex3 (GenBank Accession No.M24857); a thyroidal hormone receptor (hereinafter sometimes abbreviated as TR) xcex1 (GenBank Accession No.M24748), TRxcex2 (GenBank Accession No.M26747); vitamin D receptor (VDR) (GenBank Accession No.J03258); peroxisome proliferator-activated receptor (hereinafter sometimes abbreviated as PPAR) xcex1 (GenBank Accession No.L02932), RPARxcex2 (PPARxcex4) (GenBank Accession No.U10375), PRARxcex3 (GenBank Accession No.L40904); LXRxcex1 (GenBank Accession No.U22662), LXRxcex2 (GenBank Accession No.U14534); FXR (GenBank Accession No.U18374); MB67 (GenBank Accession No.L29263); ONR (GenBank Accession No.X75163); and NURxcex1 (GenBank Accession No.L13740), NURxcex2 (GenBank Accession No.X75918), NURxcex3 (GenBank Accession No.U12767).
A retinoid-related receptor function regulation employed here means activation or suppression of the function of a retinoid-related receptor. Activation of the function of a retinoid-related receptor means activation of the transcriptional system of a retinoid-related receptor, and a substance capable of such activation can be useful as a retinoid-related receptor ligand, a retinoid-related receptor ligand modulator, a retinoid-related receptor agonist, a modulator of a co-activator of a retinoid-related receptor, and may be any substance which gives a response similar to that generated as a result of the effect of a ligand on a retinoid-related receptor.
On the other hand, a suppression of the function of a retinoid-related receptor means a suppression of the transcriptional system of a retinoid-related receptor, and a substance capable of such suppression can be useful as a retinoid-related receptor antagonist, and may be any substance capable of suppressing a response generated as a result of the effect of a ligand on a retinoid-related receptor.
Compound (I) possesses an excellent function-activating effect especially on retinoid X receptors (RXRxcex1,RXRxcex2, RXRxcex3) and peroxisome proliferator-activated receptors (PPARxcex1, PPARxcex2(PPARxcex4), PPARxcex3) among the above retinoid-related receptors, and possesses an excellent function-activating effect on a peroxisome proliferator-activated receptor in a heterodimer receptor formed from a retinoid X receptor and a peroxisome proliferator-activated receptor, preferably a heterodimer receptor formed from RXRxcex1 and PPARxcex3. Accordingly, compound (I) can be used as a peroxisome proliferator-activated receptor ligand or a retinoid X receptor function-activating agent.
A pharmaceutical composition of the invention exhibits almost no side effects such as a body weight increase, and has a hypoglycemic effect, a hypolipidemic effect, a hypoinsulinnemic effect, an insulin sensitivity enhancing effect and an insulin resistance improving effect, thus can be employed as an agent for preventing or treating a retinoid-related receptor-mediating disease, more specifically as an agent for preventing or treating diabetes (e.g., insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes), an agent for preventing or treating hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-cholesterolemia), an anti-obesity agent, anagent for preventing or treating obesity, an insulin sensitivity enhancing agent, an insulin resistance improving agent, an agent for preventing or treating impaired glucose tolerance (IGT), and an agent for preventing transition from impaired glucose tolerance to diabetes.
Further, a pharmaceutical composition of the invention can be used as an agent for preventing or treating diabetic complications (e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia), obesity, osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia, hemopathic cachexia, endocrinopathic cachexia, infectious cachexia or cachexia induced by acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, renal diseases (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disorder), muscular dystrophy, myocardiac infarction, angina pectoris, cerebral infarction, insulin resistant syndrome, syndrome X, hyperinsulinemia-induced sensory disorder, tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer), arteriosclerosis (e.g., atherosclerosis) and as a pharmaceutical for controlling appetite or food intake.
A compound represented by formula (I) or its salt includes a novel compound such as compounds represented by any of formulae (I-1) to (I-8) or their salts. Such novel compound is employed as a pharmaceutical for treating or preventing inflammatory disease (e.g., chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, postoperative wound inflammation and swelling, neualgia, laryngopharyngitis, cystitis, hepatitis, pneumonia, pancreatitis) as well as the above diseases.
While the dose of a pharmaceutical composition of the invention may vary depending on an administration subject, an administration route, a target disease and a clinical condition, a compound of the invention as an active ingredient may be administered to an adult orally at a single dose usually of 0.05 to 100 mg/kg body weight, preferably 0.1 to 10 mg/kg body weight. This dose is administered preferably once to three times a day.
On the other hand, on the occasion of a parenteral administration, administration is conducted not more than once a day. A daily dose may be the same as on the occasion of an oral administration.
A pharmaceutical composition of the invention ca be used concomitantly with a drug such as an agent for treating diabetes, an agent for treating diabetic complications, an antihyperlipdemic agent, a hypotensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent (hereinafter abbreviated as a concomitant agent). In such case, the timing of administering a pharmaceutical composition of the invention and a concomitant agent are not particularly limited, and these may be given simultaneously or at staggered times. The dose of a concomitant agent may be selected appropriately based on the clinical dose. The ratio of compound (I) employed in a pharmaceutical composition of the invention and a concomitant agent may vary depending on an administration subject, an administration route, a target disease, a clinical condition and a combination. For example, when the administration subject is a human, the concomitant agent can be used in an amount of 0.01 to 100 parts by weight of one part by weight of compound (I).
Examples of an agent for treating diabetes include an insulin preparation (e.g., an animal insulin preparation extracted from a bovine or porcine pancreas; a human insulin preparation synthesized by a genetic engineering technique using E.coli or yeast), an insulin sensitivity-enhancing agent (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone), an xcex1-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol, emiglitol), a biguanide (e.g., phenformin, metformin, buformin), or a sulfonylurea (e.g., tolbutamide, glibenclamide, glicazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride), or other insulin secretagogues (e.g., repaglinide, senaglinide, mitiglinide, GLP-1).
Examples of the agent for treating diabetic complications include an aldose reductase inhibitor (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SK-860, CT-112), a neurotrophic factor (e.g., NGF, NT-3, BDNF), an active oxygen scavenger (e.g., thioctic acid), a cerebral vasodilator (e.g., tiapuride, mexiletine).
Examples of the antihyperlipidemic agent include a statin compound which is a cholesterol synthesis inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin), a squalene synthesis inhibitor or a fibrate compound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) having a triglyceride lowering action.
Examples of the hypotensive agent include an angiotensin converting enzyme inhibitor (e.g., captopril, enalapril, delapril) or an angiotensin II antagonist (e.g., losartan, candesartantcilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan).
Examples of the anti-obesity agent include an anti-obesity agent central acting on the central nervous system (e.g., dexfenflutramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex), a pancreatic lipase inhibitor (e.g., orlistat), xcex23 agonist: (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085), an anorectic peptide (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (e.g., lintitript, FPL-15849).
Examples of the diuretic include a xanthine derivative (e.g., theobromine sodium salicylate, theobromine calcium salicylate), a thiazide preparation (e.g., ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, pentylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide), an anti-aldosterone preparation (e.g., spironolactone, triamterene), a carbonate dehydratase inhibitor (e.g., acetazolamide), a chlorobenzensulfonamide preparation (e.g., chlorthalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide.
Examples of the chemotherapeutic agent include an alkylating agent (e.g., cyclophosphamide, ifosamide), a metabolism antagonist (e.g., methotrexate, 5-fluorouracil), an anticancer antibiotic (e.g., mitomycin, adriamycin), a plant-derived anticancer agent (e.g., vincristine, vindesine, taxol), cisplatin, carboplatin, ethopoxide. Among these, a 5-fluorouracil derivative such as Furtulon and Neo-Furtulon is preferred.
Examples of the immunotherapeutic agent include a microbial or bacterial component (e.g., muramyldipeptide derivative, Picibanil), an immunopotentiator polysaccharide (e.g., lentinan, schizophyllan, krestin), a genetically engineered cytokine (e.g., interferon, interleukin (IL)), a colony-stimulating factor (e.g., granulocyte colony-stimulating factor, erythropoietin). Among these, IL-1, IL-2 and IL-12 are preferred.
Further, an agent whose effect of ameliorating cachexia has been confirmed in animal models or clinically, namely a cyclooxygenase inhibitor (e.g., indomethacin) (Cancer Research, vol. 49, pp.5935-5939, 1989), a progesterone derivative (e.g., megestrol acetate) (Journal of Clinical Oncology, vol. 12, pp. 213-225, 1994), a glucocorticoid (e.g. dexamethasone), a metoclopramide pharmaceutical, a tetrahydrocannabinol pharmaceutical (the above references are applied to both), a fat metabolism ameliorating agent (e.g., eicosapentanoic acid) (British Journal of Cancer, vol. 68, pp. 314-318, 1993), a growth hormone, IGF-1, and an antibody to the cachexia-inducing factor TNF-xcex1, LIF, IL-6 or oncostatin M, can also be used in combination with a pharmaceutical composition of the invention.
Compound (I) employed in a pharmaceutical composition of the invention can be produced by any of the following methods: 
wherein Y is a halogen atom, and other symbols have the same meanings as above.
Examples of the halogen atom for Y include chlorine and bromine.
Compound (II) and compound (III-I) are subjected to a condensation reaction to produce a desired compound (I-A). This reaction is performed without a solvent or in a solvent which does not affect the reaction. Examples of the solvent which does not affect the reaction include an alcohol such as methanol and ethanol; an aromatic hydrocarbon such as toluene and xylene; tetrahydrofuran, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, acetic acid. Two or more of these solvents may be used as a mixture in a suitable ratio. This reaction may be performed in the presence of a base as an acid-removing agent. Examples of such base include an organic amine such as triethylamine, N-methylmorpholine and N,N-dimethylaniline; sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium acetate. The amount of the base used is 1 to 5 molar equivalent relative to compound (II). The reaction temperature is usually about 0 to 200xc2x0 C., preferably 30 to 150xc2x0 C. The reaction time is usually 0.5 to 20 hours. The desired compound (I-A) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography. 
wherein each symbol has the same meanings as above.
Compound (IV) and compound (III-2) are subjected to a condensation reaction to produce a desired compound (I-B). This reaction may be performed by a similar method to Method A. The desired compound (I-B) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography. 
wherein each symbol has the same meanings as above.
Compound (IV) and compound (III-3) are subjected to a condensation reaction to produce a desired compound (I-C). This reaction may be performed by a similar method to Method A. The desired compound (I-C) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography. 
wherein each symbol has the same meanings as above.
Compound (V) is subjected to a cyclization reaction to produce a desired compound (I-B). This reaction is performed in a solvent which does not affect the reaction. Examples of the solvent which does not affect the reaction include an alcohol such as methanol and ethanol; an aromatic hydrocarbon such as toluene and xylene; an ether such as tetrahydrofuran; an organic amine such as pyridine; an amide such as N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide; an organic carboxylic acid such as acetic acid. Two or more of these solvents may be used as a mixture in a suitable ratio.
When X is O in compound (V), this reaction is performed in the presence of a dehydrating agent. Examples of such dehydrating agent include sulfuric acid, acetic anhydride, phosphorus pentoxide, phosphorus oxychloride. While the amount of the dehydrating agent used is usually 1 to 50 molar equivalents relative to compound (V), a larger amount may also be employed in some cases.
When X is S, the reaction is performed in the presence of a sulfurizing agent. Examples of such sulfurizing agent include phosphorus pentasulfide, Lawesson""s reagent, Davy reagent. The amount of the sulfurizing agent used is usually about 1 to 50 molar equivalents relative to compound (V).
When X represents NR4, the reaction is performed in the presence of an amine (H2NR4). While the amount of the amine used is usually 1 to 50 molar equivalents relative to compound (V), a larger amount may also be employed in some cases. The reaction temperature is usually about 0 to 200xc2x0 C., preferably 30 to 150xc2x0 C. The reaction time is usually 0.5 to 20 hours. The desired compound (I-B) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography. 
wherein each symbol has the same meanings as above.
Compound (VI) is subjected to a cyclization reaction to produce a desired compound (I-4). This reaction may be performed similarly to Method D. A desired compound (I-4) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition, chromatography and the like. 
wherein each symbol has the same-meanings as above.
Desired compounds (I-A), (I-B), (I-C) and (I-D) [hereinafter abbreviated as (I-A to D) is amidated to produce a desired compound (I-E). When R5 represents an alkyl group, the reaction of compound (I-A to D) with an amine derivative (HNR6R7) is performed in a solvent which does not affect the reaction. Examples of the solvent which does not affect the reaction include an alcohol such as methanol and ethanol; an aromatic hydrocarbon such as toluene and xylene; a tertiary amine such as pyridine; an amide such as N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide. Two or more of these solvents may be used as a mixture in a suitable ratio. The reaction temperature is 20 to 200xc2x0 C., and the reaction is performed for 0.1 to 20 hours. The amount of the amine derivative used is preferably in excess of compound (I-A to D). When R5 is hydrogen atom, used is a method in which compound (I-A to D) and an amine derivative are directly condensed using dicyclohexylcarbodiimide, or a method in which a reactive derivative of compound (I-A to D) such as an acid anhydride, an acid halide (e.g., acid chloride, acid bromide), imidazolide and a mixed acid anhydride (e.g., an anhydrides with methyl carbonate, ethyl carbonate or isobutyl carbonate) is appropriately reacted with an amine derivative. Among these methods, the most convenient method is one in which an acid halide or a mixed acid anhydride is used. When an acid anhydride is used, the reaction is performed in the presence of a base, in a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as benzene and toluene; an ester such as ethyl acetate; an ether such as tetrahydrofuran; water; or a mixed solvent thereof. Examples of such base include a tertiary amine such as triethylamine, N-methylmorpholine and N,N-dimethylaniline; and an inorganic base such as sodium hydrogen carbonate, potassium carbonate and sodium carbonate. The amount of the amine derivative used is 1 to 1.5 molar equivalents relative to compound (I-A to D). The reaction temperature is xe2x88x9230 to 100xc2x0 C. The reaction time is usually 0.5 to 20 hours.
When a mixed acid anhydride is used, compound (I-A to D) is reacted with a chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate or isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate), and then reacted with an amine derivative. The amount of the amine derivative used is 1 to 1.5 molar equivalents relative to compound (I-A to D). This reaction is performed in a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as benzene and toluene; an ester such as ethyl acetate; an ether such as tetrahydrofuran; water; or a mixture thereof. The reaction temperature is xe2x88x9230 to 50xc2x0 C. The reaction time is 0.5 to 20 hours. The desired compound (I-E) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography.
Starting materials (III-1), (III-2) and (III-3) in Methods A, B and C may be prepared for example by the following Method G: 
wherein each symbol has the same meanings as above.
Compounds (VII-1), (VII-2) and (VII-3) are halogenated to produce corresponding compounds (III-1), (III-2) and (III-3). This reaction can be performed by a per se known method. This reaction is performed in the presence of a halogenating agent in a solvent which does not affect the reaction. Examples of the halogenating agent include chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide. The amount of such halogenating agent used is usually about 1 to 2 molar equivalents relative to compound (VII-1), (VII-2) or (VII-3). Examples of the solvent which does not affect the reaction include an alcohol such as methanol and ethanol; an aromatic hydrocarbon such as toluene and xylene; a halogenated hydrocarbon such as dichloromethane and chloroform; an ether such as diethyl ether and tetrahydrofuran; an amide such as N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide; a carboxylic acid such as acetic acid. These solvents may be used as a mixture in a suitable ratio. The reaction temperature is usually xe2x88x9220 to 150xc2x0 C., preferably 0 to 100xc2x0 C. The reaction time is usually 0.5 to 20 hours. Compound (III-1), (III-2) or (III-3) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography.
The starting compound (V) in Method D may be prepared for example by the following Method H: 
wherein Z is OH or a halogen atom, and other symbols have the same meanings as above. Examples of the halogen atom for Z include chlorine and bromine.
In this reaction, compound (VIII) is acylated with compound (IV) to produce compound (V). This acylation reaction can be performed by a per se known method. For example, used is a method in which compound (VIII) is directly condensed with a carboxylilc acid derivative (IX:Zxe2x95x90OH) fussing a condensing agent such as dicyclohexylcarbodiimide, or a method in which a reactive derivative of the carboxylic acid derivative such as an acid anhydride, an acid halide (acid chloride, acid bromide), imidazolide and a mixed acid anhydride (e.g., an anhydride with methylcarbonate, ethylcarbonate or isobutylcarbonate) is reacted appropriately with compound (VIII). Among these methods, the most convenient method is that in which an acid halide or a mixed acid anhydride is used. When an acid anhydride or a mixed acid anhydride is used, the reaction is performed in the presence of a base in a solvent which does not affect the reaction such as chloroform, dichloromethane, benzene, toluene, ethyl acetate and tetrahydrofuran. Examples of the base include triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogen carbonate, potassium carbonate, sodium carbonate. The amount of the acid chloride or the acid anhydride used is 1 to 5 molar equivalents relative to compound (VIII). The reaction temperature is usually xe2x88x9250 to 150xc2x0 C., preferably xe2x88x9230 to 100xc2x0 C. The reaction time is usually 0.5 to 20 hours. Compound (V) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography.
The starting compound (VI) in Method E may be produced for example by the following Method I: 
wherein each symbol has the same meanings as above.
Compound (X) is subjected to cyclization to produce compound (I). This reaction may be performed by a similar method to Method H. Compound (VI) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography.
The starting compound (IV) in Method B or C may be produced for example by the following Method J: 
wherein each symbol has the same meanings as above.
Compound (XI) is amidated to produce compound (IV-1). This reaction can be performed by a per se known method. For example, used is a method in which compound (XI) is converted into a reactive derivative such as an acid anhydride, anacid halide (acid chloride, acid bromide), imidazolide or a mixed acid anhydride (e.g., an anhydride with methylcarbonate, ethylcarbonate or isobutylcarbonate), and then reacted appropriately with ammonia. Among these methods, the most convenient method is that in which an acid halide or a mixed acid anhydride is used. When an acid anhydride or a mixed acid anhydride is used, the reaction is performed in the presence of a base in a solvent which does not affect the reaction. Examples of the base include a tertiary amine such as triethylamine, N-methylmorpholine and N,N-dimethylaniline; sodium hydrogen carbonate, potassium carbonate, sodium carbonate. As the solvent, used are a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as benzene and toluene; an ester such as ethyl acetate; an ether such as tetrahydrofuran. Ammonia may be gaseous or aqueous and is used in an amount usually of about 1 molar equivalent to a large excess. The reaction temperature is usually xe2x88x9250to 150xc2x0 C., preferably xe2x88x9230 to 100xc2x0 C. The reaction time is usually 0.5 to 20 hours. Subsequently, compound (IV-1) is thiocarbonylated to produce compound (IV-2). This reaction can be performed by a per se known method. For example, the reaction can be performed in the presence of a sulfurizing agent in a solvent which does not affect the reaction. Examples of such sulfurizing agent include phosphorus pentasulfide, Lawesson""s reagent, Davy reagent. The amount of the sulfurizing agent used is usually about 1 to 50 molar equivalents relative to compound (IV-1). Examples of the solvent include an aromatic hydrocarbon such as toluene and xylene; a halogenated hydrocarbon such as dichloromethane and chloroform; an ether such as diethyl ether and tetrahydrofuran; a tertiary amine such as pyridine; an amide such as N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide. The reaction temperature is usually 0 to 200xc2x0 C., preferably about 30 to 150xc2x0 C. The reaction time is usually 0.5 to 20 hours. Compound (IV-1) or (IV-2) thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, partition and chromatography.
As hereunder, the present invention is further described by way of Reference Examples, Examples and Experimental Examples. In the following descriptions, % means percent by weight unless otherwise specified, and a genetic engineering procedure was in accordance with a method described in Molecular Cloning [Maniatis et al, Cold Spring Harbor Laboratory, 1989] or a protocol attached to a reagent.